TNF-α and IL-6 are proinflammatory cytokines involved in the pathogenesis of various autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease, and type 2 diabetes. Blocking the biological activities of TNF-α has demonstrated clinical benefits in patients with RA and Crohn's disease, as exemplified by five antibody- or receptor-based therapeutics currently on the market. The promise of IL-6 blockade was also reinforced by the regulatory approval of one anti-IL-6R antibody for treating RA and juvenile idiopathic arthritis, with additional antibodies targeting either IL-6R or IL-6 in advanced clinical trials. As reported by Mori et al. (Int Immunol 2011; 23: 701-12), IL-6 directly activates STAT3, whereas TNF-α indirectly activates STAT3 via stimulating the expression of IL-6, which then activates STAT3 and triggers a cytokine amplification loop of IL-6, resulting in sustained STAT3 activation and chronic inflammation.
Numerous antibodies against TNF-α are commercially available and/or publicly known, including infliximab (Jansenn Biotech, Inc.), adalimumab (Abbvie, Inc.), certolizumab pegol (UCB, Inc.) and golimumab (Centocor). Although these therapeutic agents have significantly improved the treatment of certain autoimmune diseases, such as rheumatoid arthritis (RA), it has been reported that about 30% of RA patients treated with TNF inhibitors (including anti-TNFα antibodies) show little to no effect of the therapy, with about two thirds demonstrating moderate to high disease activity at 1 year after treatment (Hirabara et al., 2014, Clin Rheumatol 33:1247-54). Further, loss of therapeutic efficacy is frequently observed with anti-TNF monoclonal antibodies (adalimumab, infliximab) in patients receiving concomitant low-dose methotrexate, due to immunogenicity-related issues (Hirabara et al, 2014). A need exists for more effective compositions and methods for use of anti-TNF antibodies in treating diseases and conditions related to TNF-α.
Dysregulated IL-6 production has been demonstrated to play a pathological role in various autoimmune and chronic inflammatory diseases. Therapies against IL-6 pathways have commonly targeted the IL-6 receptor (IL-6R), including the anti-IL-6R antibodies tocilizumab, and sarilumab. Antibodies targeted directly against IL-6 have also been developed, such as olokizumab (UCB), siltuximab (Janssen), BMS-943429 (Bristol-Myers Squibb) and sirukumab (Centocor). The latter have been used against various autoimmune diseases and cancers. Following regulatory approval of tocilizumab for rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis, favorable results of off-label use have been reported in systemic lupus erythematosus, systemic sclerosis, polymyositis, vasculitis syndrome including giant cell arteritis, Takayasu arteritis, cryoglobulinemia, glomerulonephritis and rheumatoid vasculitis (see, e.g., Tanaka & Kishimoto, 2012, Int J Biol Sci 8:1227-36). While these results are promising, no antibodies against IL-6 (as opposed to IL-6R) have yet been approved for human use in any indication.
A need exists in the field for more effective, well-tolerated therapeutic agents targeted against TNF and IL-6.